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Formulation of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone with enhanced stability and bioavailability

a technology of trimethoxystyryl and sulphone, which is applied in the direction of drug compositions, inorganic non-active ingredients, capsule delivery, etc., can solve the problems of inconvenient use, inability to meet the needs of patients,

Active Publication Date: 2022-07-12
ONCONOVA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0037]In yet another aspect of the invention, there is provided an oral dosage regimen for the treatment of cancer and proliferative disorders with (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone sodium salt that reduces urotoxicity comprising administering (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, and pharmaceutically acceptable salts thereof in a first dose of about 840 mg administered approximately 1-2 hours before breakfast, followed by a second dose of about 280 mg administered about 2 hours after lunch or about 6 to about 8 hours after the first dose. In yet another aspect of the invention, there is provided an oral dosage regimen for the treatment of cancer and proliferative disorders that reduces urotoxicity comprising administering (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, and pharmaceutically acceptable salts thereof in a first dose of about 560 mg administered approximately 1-2 hours before breakfast, followed by a second dose of about 280 mg to 560 mg administered about 2 hours after lunch or about 6 to about 8 hours after the first dose.

Problems solved by technology

However, these formulations lead to unacceptable levels of impurities.
In particular, vials containing Rigosertib and PEG 400 show unacceptable levels of impurities in a matter of months when stored at room temperature and thus such vials must be stored under refrigeration, which is not convenient and adds expense.
In addition, Rigosertib in 100% PEG 400, NF when administered via infusion bags can degrade over the course of long infusion periods reducing the ability to accurately deliver the drug.
When administered orally, a common adverse event is urothelial toxicity.

Method used

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  • Formulation of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone with enhanced stability and bioavailability
  • Formulation of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone with enhanced stability and bioavailability

Examples

Experimental program
Comparison scheme
Effect test

example 1

Measurement of pH by Dilution Method and Direct Probe Method

Dilution Method

[0124]Dissolve 5 g of sample in 100 mL of carbon dioxide free water and add 0.30 mL of saturated potassium chloride solution. The detailed sample preparation technique is described in Second Supplement to USP 39-NF34; pg 8562. Measure the pH of the resulting solution at 25° C.±2° C. as described in USP 39 .

2.1 Measurement of pH by Direct Probe Method, Also Called Undiluted pH

[0125]The Solvotrode Probe (Metrohm, Cat #: 6.0339.010 or equivalent) is designed to measure the pH of non-aqueous solutions, which generally refers to solutions have ≤2.0% water. The new probe is first inspected, conditioned and tested before use following manufacturer's instructions. Then calibration is performed on the pH meter with Solvotrode electrode by use of pH standard buffer solutions of pH 4, 7, 9 and 12. The pH of a pH 13 buffer solution (0.2 M KCl adjusted to pH to 13 by 0.2 M NaOH) was checked as a bracketing standard. The v...

example 2

[0126]Manufacture and Long Term Stability of non-pH adjusted and pH-adjusted drug product for Rigosertib (ON 01910.Na) Injection

Introduction

[0127]Rigosertib (ON 01910.Na) Injection (75 mg / mL) was manufactured initially without pH adjustment. The drug product formulation is a non-aqueous solution of Rigosertib in PEG 400. The stability of the drug product was significantly improved by increasing the drug product pH by addition of NaOH. The manufacturing process and stability were compared between the non-pH adjusted drug products (ZBN060 & ZBN061) and pH adjusted drug products (ZBP026 & ZBR006). Also provided is data on aqueous solutions of Rigosertib in 25% PEG 400 / 75% phosphate buffer, pH 10.0 and 50% PEG 400 / 50% phosphate buffer, pH 10.0 as shown in Examples VIII and IX of U.S. Pat. No. 8,476,320 B1.

[0128]Manufacture Process

[0129]ON 01910.Na non-pH adjusted concentrate was prepared by adding small amounts of ON 01910.Na API slowly to PEG 400. The contents were mixed until complete...

example 3

[0136]Oral Absorption of Rigosertib in Dogs after Dosing with Rigosertib Solution

Introduction

[0137]Rigorsertib (ON 01910.Na) oral solutions were dosed to fasted non-naïve male beagle dogs and the absorptions was compared amongst two formulations.

1. Experimental Procedure

[0138]Two formulation of oral Rigosertib solutions were prepared:[0139]A. ON 01910.Na 75 mg / mL regular pH concentrate (final pH by USP : 7.11)[0140]B. ON 01910.Na 75 mg / mL high pH concentrate (final pH by USP : 10.12)

2.1. Preparation of Drug Product Formulation

[0141]ON 01910.Na non-pH adjusted concentrate was prepared by adding ON 01910.Na API slowly into PEG 400 and stirred using overhead stirring until a homogenous solution was obtained. The drug product was then filtered through a 0.45 μm membrane filter. The pH of final drug product was measured dilution method (final pH is 7.11) and then stored at refrigerated condition. The high pH formulation was prepared by adding 4.0 N NaOH into PEG 400 vehicle first and the...

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Abstract

Pharmaceutical compositions of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof are described as well as methods of their use, and a dose regimen of (E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone, sodium salt to reduce the incidence of urothelial toxicity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is filed under 35 U.S.C. § 371 as the U.S. national phase of International Patent Application No. PCT / US2018 / 027514, filed Apr. 13, 2018, which designated the United States, and which claims the benefit of U.S. Provisional Application No. 62 / 485,355 filed Apr. 13, 2017; International Patent Application No. PCT / US2018 / 027514, filed Apr. 13, 2018, is a continuation-in-part of U.S. patent application Ser. No. 15 / 688,320, filed Aug. 28, 2017, which issued as U.S. Pat. No. 10,098,862 B2 on Oct. 16, 2018, and which claims the benefit of U.S. Provisional Application No. 62 / 485,355 filed Apr. 13, 2017; and International Patent Application No. PCT / US2018 / 027514, filed Apr. 13, 2018 is a continuation-in-part of International Application No. PCT / US2017 / 048890, filed Aug. 28, 2017, which claims the benefit of U.S. Provisional Application No. 62 / 485,355 filed Apr. 13, 2017; and all of these applications are hereby incorporated ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/145A61K47/10A61K9/00A61P35/02A61K9/48
CPCA61K31/145A61K9/0053A61K9/4858A61K47/10A61P35/02A61K9/0019A61K9/4866A61K31/196A61K31/198A61P35/00A61K47/02A61K9/4825A61K31/197
Inventor MANIAR, MANOJ
Owner ONCONOVA THERAPEUTICS
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